The treatment of peptic ulcer has changed in the last few years to include the use of anti-secretory agents which selectively block histamine H.sub.2 -receptors. The subdivision of histamine receptors into two groups, the H.sub.1 - and H.sub.2 -receptors, was proposed by Ash and Schild (Brit. J. Pharmacol. Chemother, 1966, 27, 427) and Black et al (Nature 1972, 236, 385). The H.sub.1 -receptor is involved in the bronchial and gastrointestinal smooth muscle stimulative action of histamine. Drugs which block this action are labelled "antihistamines" (e.g. mepyramine). Black et al, cited above, described the group of substances which act at histamine receptors other than the H.sub.1 -receptor as the H.sub.2 -receptors. Blocking the action of histamine at the H.sub.2 -receptors will selectively block histamine's stimulative action on gastric acid secretion and heart rate. Burimamide was the first clinically effective H.sub.2 -receptor antagonist inhibiting gastric secretion in man, but its oral absorption is poor. Subsequent studies developed the orally active Metiamide, the side effects of which limited clinical use, and Cimetidine which has been marketed as an anti-ulcer drug. A number of classes of heterocyclic chemical compounds have been reported as H.sub.2 -receptor antagonists, for example, those disclosed in U.S. Pat. Nos. 4,104,381, 4,279,819, 4,323,566, and British published patent application GB 2067987A, the disclosures of which are incorporated by reference.
Another method for the prevention or treatment of gastric ulcer comprises the use of drugs which neither neutralize nor inhibit the secretion of gastric acid. These drugs are described as "cytoprotective" agents and constitute a class of anti-ulcer compounds which function to enhance the normal defense mechanisms of the body, rather than to reduce normal body secretions. Prostaglandins have been implicated in the mechanism of cytoprotection by a number of workers in the field. See, the discussion of cytoprotection in Robert, Andre, "Prostaglandins and Digestive Diseases", Advances in Prostaglandin and Thromboxane Research, Vol. 8 (Raven Press, N.Y. 1980), and Robert et al, "Cytoprotection by Prostaglandins in Rats", Gastroenterology, 77, 433-443 (1979), hereby incorporated by reference. Drugs, other than prostaglandins, which exhibit cytoprotective activity include carbenoxolone sodium, reported to exhibit undesirable side effects, such as edema, diastolic hypertension or hypokalemia, and the thiazol-2-yl-carbamoylcarboxylic acids, esters and imides described in U.S. Pat. No. 4,321,372.
The compounds of the present invention are a class of novel bicyclic heterocyclics which exhibit anti-secretory activity as H.sub.2 -receptor antagonists and cytoprotective activity.